Most peptide hormones on target cells and are then internalized. We have examined the possibility that there is a function for internalized. We have examined the possibility that there is a function for internalized cytokines. Various cytokines were microinjected into appropriate target cells, and single cell assays were then performed to analyzed the response. We observe that microinjection of interferon-gamma (IFN-gamma) into macrophages induces synthesis of granulocyte-macrophage colony-stimulating factor, and this subsequently induces Ia-expression on other macrophages. Microinjection of tumor necrosis factor (TNF) killed several types of cells. On the other hand microinjection of interleukins 1 and 2 did not elicit detectable responses from appropriate target cells. Based on the novel observations with IFN-gamma and TNF, we propose a new role for some cytokine receptors: transport of the cytokine to an intracellular site of action. Interleukin 1 (ILl) has been previously implicated in the activation of T lymphocytes, and has been thought to be provided by antigen-presenting cells (APC) to the T cell, along with processed antigen and Ia. We previously observed that the opposite was true for T cell clones: they produce their own ILl. We now observe that this ILl derived from T cells performs a crucial, previously unrecognized role in antigen presentation: ILl induces the appearance of essential structures on antigen-presenting cells. Thus, if APC are fixed with a cross-linking agent prior to exposure to ILl, they fail to stimulate T cell proliferation: IL1 treatment results in expression of new structures, permitting fixation of the APC.